title: Distinct disease phenotypes linked to different combinations of GAA mutations in a large late-onset GSDII sibship.
abstract: BACKGROUND
  Glycogenosis type II (GSDII or Pompe disease) is an autosomal recessive disease, often characterized by a progressive accumulation of glycogen within lysosomes caused by a deficiency of α-1,4-glucosidase (GAA; acid maltase), a key enzyme of the glycogen degradation pathway. To date, more than 326 different mutations in the GAA gene have been identified in patients with GSDII but the course of the disease is difficult to be predicted on the basis of molecular genetic changes. Studies on large informative families are advisable to better define how genetics and non genetics factors like exercise and diet may influence the clinical phenotype.
  
  
  RESULTS
  In this study, we report on clinical, instrumental, and pathological features as well as on molecular analysis of a family with 10 out of 13 siblings affected by late-onset Pompe disease. Three mutations segregated in the family, two of which are novel mutations. Siblings showing a more severe phenotype were compound heterozygous for c.118C > T [p.R40X] and c.2647-7G > A [p.N882fs] on GAA, whereas, two patients showing a mild phenotype were compound heterozygous c.2647-7G > A [p.N882fs] and c.2276G > C [p.G759A] mutations. Quantitative expression analysis showed, in the patients carrying p.R40X/ p.N882fs, a significant (p 0.01) correlation between the levels of expression of the mutated allele and the age at onset of the disease.
  
  
  CONCLUSIONS
  As far as we know, this is the largest informative family with late-onset Pompe disease described in the literature showing a peculiar complex set of mutations of GAA gene that may partially elucidate the clinical heterogeneity of this family.
authors.affiliation: Department of Medical Sciences, Surgery, Neurological, Metabolic and Aging, Second University of Naples, Naples, Italy. simone.sampaolo@unina2.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Sampaolo
authors.forename: Teresa
authors.initials: T
authors.lastname: Esposito
authors.forename: Olimpia
authors.initials: O
authors.lastname: Farina
authors.forename: Daniela
authors.initials: D
authors.lastname: Formicola
authors.forename: Daria
authors.initials: D
authors.lastname: Diodato
authors.forename: Fernando
authors.initials: F
authors.lastname: Gianfrancesco
authors.forename: Federica
authors.initials: F
authors.lastname: Cipullo
authors.forename: Gaetana
authors.initials: G
authors.lastname: Cremone
authors.forename: Mario
authors.initials: M
authors.lastname: Cirillo
authors.forename: Luca
authors.initials: L
authors.lastname: Del Viscovo
authors.forename: Antonio
authors.initials: A
authors.lastname: Toscano
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Iorio
mesh_terms: D000293:Adolescent; D000328:Adult; D015519:Bone Density; D002648:Child; D004594:Electrophysiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006009:Glycogen Storage Disease Type II / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult; D000520:alpha-Glucosidases / Q000235:genetics*
chemical_list: C509951:GAA protein, human; D000520:alpha-Glucosidases